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Major side effects of systemic glucocorticoids

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Major side effects of systemic glucocorticoids


Authors
Kenneth G Saag, MD, MSc
Daniel E Furst, MD
Section Editor
Eric L Matteson, MD, MPH
Deputy Editor
Paul L Romain, MD
Disclosures
All topics are updated as new evidence becomes
available and our peer review process is complete.
Literature review current through: Mar 2013. | This
topic last updated: Apr 8, 2013.
INTRODUCTION — Glucocorticoids are important in
the treatment of many inflammatory, allergic,
immunologic, and malignant disorders, and the
toxicity of glucocorticoids is one of the commonest
causes of iatrogenic illness associated with chronic
inflammatory disease. Recognition of these toxicities,
many of which are similar to the findings in
spontaneous (endogenous) Cushing’s syndrome, is of
value in their prevention and management.
(See"Epidemiology and clinical manifestations of
Cushing's syndrome" .)
Numerous toxicities, or adverse effects (AEs), have
been attributed to glucocorticoids ( table 1 ).
However, the attribution of causality to the
glucocorticoids alone cannot always be clearly
established. Other factors that may contribute to such
AEs include the nature and severity of the underlying
disease being treated and the other medications being
administered concurrently. Estimates of the frequency
and severity of AEs, as well as the respective dose
and duration of therapy that may result in such AEs,
are also limited by the modest number of prospective
trials that address this question. The benefits of these
medications in critical illness and the morbidity of
some of the AEs make such prospective data
acquisition in randomized trials of sufficient duration
unlikely.
The AEs seen specifically with systemic (oral and
parenteral) glucocorticoid therapy will be reviewed
here. The AEs resulting from the use of inhaled,
topical, and intraarticular glucocorticoids;
glucocorticoid withdrawal (retirada); and the clinical
manifestations of endogenous glucocorticoid excess
are discussed in detail separately. (See "Major side
effects of inhaled glucocorticoids" and "General
principles of dermatologic therapy and topical
corticosteroid use", section on 'Side effects' and "Joint
aspiration or injection in adults:
Complications" and "Glucocorticoid
withdrawal" and "Epidemiology and clinical
manifestations of Cushing's syndrome" .)
MECHANISM OF ADVERSE EFFECTS — The
adverse effects (AEs) of glucocorticoids are more
common in patients receiving these drugs in high
doses or over a long period of time. Glucocorticoids
used in chronic disease
(eg, prednisone or prednisolone ) do not have
significant mineralocorticoid, androgenic, or
estrogenic activity; thus, their major AEs result from
inhibition of hypothalamic-pituitary-adrenal function
and the development of iatrogenic Cushing’s
syndrome. The relative frequency of features of
endogenous Cushing’s syndrome and the iatrogenic
syndrome vary. (See "Pharmacologic use of
glucocorticoids", section on 'Complications of chronic
use' and "Epidemiology and clinical manifestations of
Cushing's syndrome" .)
The effects of glucocorticoids are mediated by
cytosolic glucocorticoid receptors and result from both
genomic and nongenomic mechanisms that also have
a role in the therapeutic effects of these agents [ 1-
3 ]. The adverse effects appear to result largely from
transactivation that leads to increased expression of
regulatory and antiinflammatory proteins [ 2 ]; by
contrast, many of the clinically desirable effects
appear to result primarily from transrepression, which
results in the decreased production of
proinflammatory proteins. Nongenomic effects of
glucocorticoids include rapid, nonspecific interactions
of glucocorticoids with cellular membranes,
nongenomic effects medicated by cytosolic
glucocorticoid receptors, and specific interactions with
membrane-bound glucocorticoid receptors [ 2 ].
DOSE EFFECTS — Glucocorticoid toxicity is generally
related to both the average dose and cumulative
duration of use, although, for most toxicities, a
“threshold” dose or duration has not been established
[ 4 ]. Controversy exists over the relative safety of
“low-dose” glucocorticoid use (less than or equal to
10 mg/day of prednisone or equivalent) in chronic
conditions such as rheumatoid arthritis (RA). Several
large retrospective reviews have shown that long-
term glucocorticoid use, even in low doses, is a
significant independent predictor of numerous serious
AEs and that risk is both dose and time dependent
[ 5,6 ]. Other analyses note a paucity of evidence
documenting toxicity from the use of very low doses
of glucocorticoids (eg, prednisone <5mg/day), such
as those sometimes used for the treatment of
rheumatoid arthritis [ 4 ]. The following studies
illustrate the range of observations regarding the
influence of dose and duration of therapy:

 One study of patients with RA found that the


average daily prednisone dose was the
strongest predictor of a serious AE potentially
attributable to glucocorticoid therapy (odds ratio
= 4.5 for 5 to 10 mg, and 32.3 for 10 to 15 mg)
( figure 1 ) [ 5 ]. This glucocorticoid-AE
association persisted after statistical adjustment
for significant disease severity factors, such as
the presence of rheumatoid nodules and bony
erosions. However, glucocorticoid use in RA is
associated with disease severity and degree of
disability, which makes the results of
observational uncontrolled studies more difficult
to interpret with a high level of confidence [ 7 ].
 A review of the published literature and of the
adverse event (AE) data from four randomized
trials of low dose glucocorticoids ( prednisone or
equivalent 5 to 10 mg/day) involving 568
patients with RA found a paucity of high quality
evidence regarding the degree of risk from low-
dose glucocorticoids and only small numbers of
AEs associated with glucocorticoid use in the
randomized trials [ 4 ]. However, the
prospective trials were not primarily designed to
detect adverse effects, and patients were
followed for only two years. The following
observations were made in the analysis of these
four randomized trials:

 One study showed increased hyperglycemia


associated with use of low-dose glucocorticoids,
but no cases of new onset diabetes were
reported.
 Low-dose glucocorticoid use was associated with
an increase in body weight of 4 to 8 percent
over two years, which reached significance
compared with placebo in two of the four trials.
 In the two studies involving a total of 273
patients in which ophthalmologic examinations
were performed, there were 4 patients on low-
dose glucocorticoids reported with glaucoma,
but there were no cases among in the controls.
The incidence of cataracts was not increased.
 Low-dose glucocorticoid therapy, when compared
with placebo, was not associated during the
trials with an increased loss of bone mineral
density, any reports of avascular necrosis,
myopathy, decreased libido, excess
cardiovascular events or heart disease,
increased blood pressure, serious cutaneous
adverse effects, upper GI ulcers or bleeding,
pancreatitis, increased risk of infection,
psychosis, or mood disturbance.

 In a mail survey of 6517 patients receiving


glucocorticoid treatment (mean dose ± standard
deviation [SD] of prednisone equivalent of 16 ±
14mg/day) for various conditions for at least 60
days, over 90 percent of patients reported at
least one of eight AEs commonly associated with
glucocorticoid use [ 8 ]. At least one AE rated as
very bothersome was reported by 55 percent of
patients. Weight gain was the most common AE
reported (70 percent). Skin bruising or thinning
and sleep disturbance were also common.
Cataracts occurred in 15 percent, and fractures
occurred in 12 percent.

There was a strong association with cumulative


glucocorticoid dose of all eight AEs that were
assessed. In patients receiving low doses
(prednisone ≤7.5 mg/day), increasing duration
of use (greater than 90 days) was associated
with acne, skin bruising, weight gain, and
cataracts. Increases in the daily dose within the
low-dose range (0 to 7.5 mg/day) were more
strongly associated with fractures and sleep
disturbance than was increased duration of use.
The degree of bias introduced by a low response
rate (of 38 percent) is unknown.
TOXICITY OF SYSTEMIC GLUCOCORTICOIDS BY
ORGAN SYSTEM OR SYMPTOM COMPLEX —
Glucocorticoids have adverse effects (AE) on many
organ systems ( table 1 ). AEs range from those that
are not necessarily serious but are displeasing to
patients (eg, Cushingoid appearance) to those that
are life-threatening (eg, serious infections).
Unfortunately, some AEs, such as accelerated
reductions in bone mineral density or early cataracts,
may be largely asymptomatic until later
manifestations develop that require medical attention
(eg, acute vertebral collapse, cataract requiring
surgical extraction). Estimates of the frequency of
particular adverse effects vary between studies and
depend in part on the specific condition being treated
and on the glucocorticoid treatment regimen being
used [ 9 ]. With the exception of cataracts, a potential
acceleration in atherosclerotic vascular disease, and,
to a lesser degree, bone effects (osteoporosis and
osteonecrosis), all glucocorticoid toxicity is at least
partially reversible over time with glucocorticoid
discontinuation.
Skin and soft tissues — Among the most common
toxicities attributable to glucocorticoids are skin
thinning and purpura. Skin changes were seen in 46
percent of patients treated for three months
with prednisone at doses greater than 20 mg daily
[ 10 ]. Glucocorticoid-associated purpura often affects
the sun exposed areas of the dorsum of the hand and
forearm and is not accompanied by palpable swelling.
Data from a large arthritis cohort suggest that 32
cases of purpura develop for every 1000 patient-years
of follow-up [ 11 ]. (See "Approach to the patient with
macular skin lesions", section on 'Solar purpura
(senile purpura)' .)
Non-melanoma skin cancers (squamous cell and basal
cell types) may be more frequent in patients who use
oral glucocorticoids. The risk of squamous and basal
cell skin cancer was increased in oral glucocorticoid
users compared with age and sex matched case
controls without skin cancer in one study (odds ratios
2.31 and 1.49, respectively) [ 12 ]; a similar
increased risk was noted in another retrospective
study population with observed to expected incidence
rates (standardized incidence ratio or SIR) of 2.45 and
1.52, respectively [ 13 ]. Other dermatologic AEs
include “steroid acne,” alopecia, hypertrichosis, and
striae.
Cushingoid appearance and weight gain — The
development of Cushingoid features (redistribution of
body fat with truncal obesity, buffalo hump, and moon
face) and weight gain are quite troubling to patients;
the risk of these complications is both dose and
duration dependent:

 In an observational study of 799 patients with


rheumatoid arthritis, adverse effects in patients
treated with glucocorticoids for at least six
months were compared with those in patients
who had not received glucocorticoids for at least
12 months at the time of evaluation; weight
gain was more frequent in patients treated with
at least 5 mg/day of prednisone or equivalent,
compared with those who had not received any
for at least 12 months (22.4 versus 9.5 percent)
[ 14 ]. However, there was a threshold effect,
such that the rate of weight gain was not
increased in those who took less than
5 mg/day (8.7 percent) or further increased at
doses greater than 7.5 mg/day (21.3 percent)
[ 14 ].

Cushingoid features showed a linear increase in


frequency with dose rather than a threshold
effect. Only 2.7 percent of patients who had not
received glucocorticoids in the prior 12 months
exhibited such changes, compared with 4.3,
15.8, and 24.6 percent of patients who had
received <5, 5 to 7.5, and >7.5 mg/day of
prednisone or equivalent, respectively.
 In a survey of 2167 long-term users of
glucocorticoids (mean prednisone equivalent
dose ± SD of 16 ± 14 mg/day for ≥60 days),
weight gain was the most common self-reported
adverse event (70 percent of patients) [ 8 ]. In
those on ≤7.5 mg/day of prednisone or
equivalent, increasing duration of use was
significantly associated with weight gain.
 In an analysis of four prospective trials of
glucocorticoids in rheumatoid arthritis, the use
of 5 to 10 mg/day of prednisone or equivalent
over two years was associated with an increase
of mean body weight of 4 to 8 percent [ 4 ].

The Cushingoid appearance may occur within the first


two months of therapy. Alternate day therapy, which
causes less hypothalamic pituitary adrenal axis
suppression, may result in a lower incidence of
Cushingoid changes. However, the likelihood of
developing such changes remains dose dependent in
our experience, and alternate day therapy does not
prevent their occurrence.
Factors which may contribute to increased weight also
include an increased appetite, a common side effect of
glucocorticoid therapy, and an increase in food intake
for symptomatic relief in patients with gastropathy or
peptic ulcer disease [ 15 ]. (See "Epidemiology and
clinical manifestations of Cushing's syndrome", section
on 'Progressive obesity' and 'Gastrointestinal
tract' below.)
Eye — The risk of both cataracts and glaucoma is
increased in patients on glucocorticoids and is dose-
related [ 4 ]. Patients on prolonged moderate- to
high-dose therapy should be examined periodically by
an ophthalmologist to promote early detection of
cataracts and glaucoma. (See "Cataract in
adults"and "Open-angle glaucoma: Epidemiology,
clinical presentation, and diagnosis" and "Angle-
closure glaucoma" .)
Cataracts commonly occur after prolonged
glucocorticoid use. These cataracts share the following
features:

 They occur in a posterior subcapsular location and


can usually be distinguished from senile
cataracts.
 They are often bilateral and develop slowly.
 Children are more susceptible than adults.
(See "Cataract in children", section on
'Glucocorticoids' .)
There may be no minimal safe dose with respect to
the risk of cataract formation, although risk is dose
and time dependent and is more common
withprednisone doses greater than 10 mg/day or with
medications that have been administered for more
than one year [ 16-18 ]. In a study that evaluated
122 patients with RA taking a mean dose of
prednisone of 8.0 mg/day for an average of 6.9 years,
29 percent developed cataracts compared with 18
percent of matched controls [ 6 ]. Another study of
patients with rheumatoid arthritis receiving a mean
dose of 6 mg of prednisone daily for a mean of 6
years also found cataracts more common in patients
on glucocorticoids than in patients not using
prednisone (15 versus 4.5 percent) [ 5 ].
Glucocorticoids can also increase intraocular pressure,
but these effects can usually be controlled with
appropriate medical therapy [ 4,19 ]. This form of
glaucoma occurs most commonly in patients who use
glucocorticoid eye drops, although it has been
observed in chronic and, to a lesser extent, acute
systemic glucocorticoid use [ 20 ]. The risk of
glaucoma or worsening intraocular pressure is greater
in patients on glucocorticoids who are otherwise
predisposed to this disorder or who have certain
comorbidities, including those with a positive family
history of glaucoma diabetes mellitus or high myopia
[4,21 ]. In patients with pre-existing open- or closed-
angle glaucoma, the use of glucocorticoids will
frequently aggravate the condition (46 to 92 and 65
percent, respectively) [ 19,22 ].
Exophthalmos and swelling of the lids and ocular
muscles are rare ophthalmologic complications of
glucocorticoids [ 23,24 ].
A rare adverse effect of systemic, local, or even
topical use of glucocorticoids is central serous
chorioretinopathy [ 25-27 ]. This type of
chorioretinopathy is associated with edema formation
that can separate the retina from the choroid.
Reduction of glucocorticoid dose is the most important
element of treatment, if it can be done without
causing a dangerous exacerbation of the disease that
is being treated with the glucocorticoids [ 28 ].
Cardiovascular disease — Glucocorticoid use is
associated with an increased risk of serious adverse
cardiovascular events, particularly ischemic heart
disease and heart failure, just as atherosclerosis is
accelerated and cardiovascular risk is increased in
patients with hypercortisolism due to Cushing's
disease; this risk is dose dependent and may be low
or absent in patients on low-dose glucocorticoid
therapy [ 29 ]. The relative risks of ischemic heart
disease versus heart failure or stroke may differ
depending upon the condition being treated with
glucocorticoids [ 30,31 ]. (See "Epidemiology and
clinical manifestations of Cushing's syndrome" .)
Therapeutic use of supraphysiologic doses of
glucocorticoids has been associated with increased
rates of myocardial infarction, stroke, heart failure,
and all-cause mortality. The following observations
have been made:
 Increased cardiovascular disease was associated
with glucocorticoid use at doses
≥7.5 mg/day of prednisone in a population-
based study that compared 68,781 patients for
whom glucocorticoids were prescribed with
82,202 nonusers; none of these patients had
been hospitalized previously for cardiovascular
disease [ 29 ]. The rate of cardiovascular
disease (a composite of myocardial infarction,
angina, coronary revascularization,
hospitalization for heart failure, transient
ischemic attack or stroke), adjusted for other
measured risk factors, was significantly higher
in patients who were prescribed high doses of
glucocorticoids (defined as ≥7.5 mg/day of
prednisone or its equivalent), compared with
those who had not received glucocorticoids
(absolute risk difference 59 events per 1000
patient-years, adjusted rate ratio 2.6). Such risk
was not increased in patients receiving less than
7.5 mg prednisone daily.

Risk of the composite end point was higher for


patients who had continuing prescriptions than
for those receiving intermittent glucocorticoid
prescriptions and was higher for users of
glucocorticoids during the six months prior to
the event compared with use at an earlier time.

The risks of heart failure, myocardial infarction,


a combination of stroke and transient ischemic
attacks (TIA), and all-cause mortality were each
significantly higher for those prescribed high-
dose glucocorticoids (rate ratios of 3.7, 3.3, 1.7,
and 7.4, respectively) [ 29 ]. The risk of heart
failure appeared to increase with higher daily
glucocorticoid doses.
 Similar associations between glucocorticoid use
and ischemic heart disease and heart failure
were noted in another large retrospective case-
control study [ 30 ]. Current glucocorticoid use
was associated with significantly increased risks
of heart failure and ischemic heart disease
(adjusted odds ratios 2.7 and 1.2, respectively)
but not with stroke or TIA. The risk was greater
at higher doses and with current, compared with
past, use. The relation of current glucocorticoid
use with heart failure was greatest for patients
with chronic obstructive pulmonary disease
(COPD) compared with patients with RA or with
neither RA nor COPD. The risk of ischemic heart
disease for current users was increased in both
patients with RA and those with COPD, but not
in patients with neither RA nor COPD
 Adverse cardiovascular outcomes, including
myocardial infarction, heart failure, peripheral
vascular disease, and cerebrovascular disease,
were not significantly increased in patients
treated with glucocorticoids for polymyalgia
rheumatica and subsequently followed for a
median of 7.6 years, compared with patients
treated with nonsteroidal antiinflammatory
drugs (NSAIDs) [ 31 ]. A trend for a protective
effect of glucocorticoids was seen compared
with NSAID treatment, particularly when the
outcomes were taken together.
The development of iatrogenic Cushing syndrome may
be a marker for patients at a higher risk of
cardiovascular disease. A cohort of 547 patients
diagnosed with Cushing syndrome associated with
glucocorticoid use in a large general practice database
had a significantly greater risk of a cardiovascular
event compared with 3231 age- and sex-matched
patients, who were receiving similar doses of
glucocorticoids (initial median dose of 25 to 28
mgprednisone , interquartile range of 5 to 45 mg, and
median duration of 8.4 to 9.6 months, interquartile
range of 2.5 to 25.5 months) but who did not have a
diagnosis of Cushing syndrome, and compared with
3282 patients who did not receive glucocorticoids
(incidence rates of risk per 100 person-years: 15.1,
95% CI 11.8-18.4, versus 6.4, 95% CI 5.5-7.3,
versus 4.1, 95% CI 3.4-4.8) [ 32 ]. The increased
risks compared with both sets of controls remained
after adjustment for multiple potential confounding
variables (adjusted hazard ratios of 2.74, 95% CI
2.06-3.62, and 4.16, 95% CI 2.98-5.82).
An association of glucocorticoid use with risk of atrial
fibrillation and flutter has been reported in two small
observational studies and in a larger population-
based, case-control study [ 33-35 ]. In the latter
study, current glucocorticoid use was more common
among 20,221 patients with atrial fibrillation or flutter
than in 202,130 population controls (6.4 versus 2.6
percent) [ 35 ]. Currently using glucocorticoids was
associated with a significant increased risk of atrial
fibrillation or flutter, compared with never having used
glucocorticoids (adjusted odds ratio, OR, 1.9). Risk
was increased for new users and long-term users, but
not for former users (OR 3.6, 1.7, and 1.0,
respectively), and was unrelated to whether or not
pulmonary or cardiovascular disease was present.
Serious adverse cardiovascular toxicities, including
sudden death, have been reported in occasional
patients who have been given pulse infusions of
glucocorticoids (eg, 1 g/day of methylprednisolone for
multiple infusions) [ 36 ]. In many of these cases,
however, it was difficult to determine whether this AE
was more likely attributable to glucocorticoids or to
the underlying disorder necessitating the therapy.
Thus, cardiac monitoring is indicated in patients with
significant cardiac disease who are treated with pulse
glucocorticoid therapy, especially those on diuretics,
the use of which may also be associated electrolyte
disturbances such as hypokalemia.
Lipids — The effect of glucocorticoids on
atherosclerotic vascular disease is thought to be
mediated in part by elevated lipoprotein levels.
However, the results of studies performed to analyze
this issue have had mixed results, and beneficial
effects of glucocorticoids on dyslipidemia have also
been observed. In one report, moderate- to low-
dose prednisone (20 mg/day tapered to
5 mg/day over three months) had no significant
adverse effect on lipoprotein levels if other risk factors
were taken into account [ 37 ]. Another observational
study concluded that glucocorticoid use was
associated with a more favorable lipid profile in older
adults (≥60 years) [ 38 ]. Studies in patients with
systemic lupus erythematosus (SLE) have indicated
that the adverse effects of glucocorticoids on lipid
profiles are dose dependent, occurring only at
prednisone doses greater 10 mg/day [ 39-41 ].
Interpretation of these data is complicated by the
difficulty of distinguishing effects due to disease
activity, which itself may be associated with increased
cardiovascular risk and lipid abnormalities, from
effects directly related to the medications themselves
[ 42 ].
Glucocorticoids may act by leading sequentially to
peripheral insulin resistance, hyperinsulinemia, and
increased hepatic VLDL synthesis. However,
glucocorticoid-induced reduction in ACTH release also
contributes to the lipid changes. In one report, for
example, the administration of ACTH for three weeks
to nine hyperlipidemic, glucocorticoid-treated patients
(five of whom were transplant recipients) led to
substantial reductions in total and LDL-cholesterol and
triglycerides and to an increase in HDL-cholesterol
[ 43 ]. ACTH may act, in part, by up-regulating LDL
receptor activity.
Gastrointestinal tract — Glucocorticoids
independently increase the risk for a number of
adverse gastrointestinal (GI) events, such as gastritis,
ulcer formation, and GI bleeding. However, the risk of
peptic ulcer disease due to glucocorticoids alone is
low, rises significantly when they are used in
combination with nonsteroidal antiinflammatory drugs
(NSAIDs), and is also lower than the risk with NSAIDs
alone [ 44,45 ].
The estimated relative risks of glucocorticoids alone
vary from 1.1 (not significant) to 1.5 (marginally
significant) [ 44,45 ]. However, the combination of
glucocorticoids and NSAIDs results in a synergistic
increase in the incidence of GI events as shown by the
following findings from two meta-analyses:

 Glucocorticoid use is associated with a nearly


twofold increased risk of a gastrointestinal AE
among patients also taking NSAIDs when
compared with those who use NSAIDs alone
[ 46 ].
 The use of NSAIDs and glucocorticoids is
associated with a fourfold increased risk of a
gastrointestinal AE compared with nonuse of
either drug [ 45].

Whether substitution of a selective COX-2 inhibitor for


a nonselective NSAID would lower this risk is unclear.
We suggest NOT using prophylaxis against
gastrointestinal bleeding in patients taking
glucocorticoids alone. By contrast, patients taking
glucocorticoids in combination with aspirin or other
NSAIDs may require prophylaxis. (See "NSAIDs
(including aspirin): Primary prevention of
gastroduodenal toxicity" .)
There are a variety of other GI complications that can
occur in glucocorticoid users, including visceral
perforation [ 47-49 ] and hepatic steatosis (fatty liver)
that can rarely lead to systemic fat embolism
[ 50,51 ].
Glucocorticoids may mask the symptoms of serious
gastrointestinal disease, an effect that may account,
in part, for the increased risk of perforated sigmoid
diverticular abscess associated with their use [ 49 ].
Pancreatitis — The role of glucocorticoids in causing
acute pancreatitis is uncertain. While there is some
evidence suggesting an etiologic role for
glucocorticoids [ 52-54 ], other studies, particularly in
patients with systemic lupus erythematosus, have
shown that the disease is causative, rather than the
drugs, which may be beneficial therapeutically
[ 55,56 ]. (See "Etiology of acute pancreatitis" .)
A large population-based nested case control study
analyzed 6161 cases of acute pancreatitis and 61,637
controls. It found an increased risk for acute
pancreatitis among the current users of oral
glucocorticoids compared with nonusers (OR 1.53,
95% CI 1.27-1.84), but whether the analysis was able
to adequately control for all relevant confounders was
not clear [ 54 ]. Risk was highest from 4 to 14 days
after the drug was dispensed but was not elevated
prior to that interval; risk gradually decreased after
two weeks, returning to baseline within one to two
months. Large prospective epidemiologic studies will
be required to more clearly define the relationship of
newly started glucocorticoid therapy with the onset of
pancreatitis, particularly in the absence of data from
randomized trials. The risk of pancreatitis in patients
receiving long-term glucocorticoids also remains
uncertain.
Kidney and systemic hemodynamics —
Glucocorticoids have a number of dose dependent
effects on renal function and systemic hemodynamics:
 Higher dose glucocorticoids commonly promote
fluid retention, a particular concern to patients
with underlying heart or kidney disease. This is
not a problem in normal subjects because of the
phenomenon of mineralocorticoid escape which
prevents progressive fluid overload.
(See "Clinical features of primary
aldosteronism" .)
 Glucocorticoid therapy can raise the blood
pressure in both normotensive and hypertensive
subjects. How this occurs is not well-understood
[ 57,58]. (See "Epidemiology and clinical
manifestations of Cushing's syndrome", section
on 'Hypertension and cardiovascular risk' .)

Long-term use of prednisone in patients with RA


may be associated with a higher risk of
hypertension [ 59,60 ]. However, in patients
receiving low doses of glucocorticoids (eg,
10 mg/day of prednisone), significant
hypertension may be better explained by age
and initial blood pressure than by the
glucocorticoids themselves [ 61 ].
 Kaliuresis occurs early with glucocorticoid
therapy. Rapid administration of high doses can
result in the development of hypokalemia and
metabolic alkalosis. However, clinically
significant hypokalemia is uncommon with
routine exogenous glucocorticoid use.

Genitourinary and reproductive system — High


doses of glucocorticoids can cause menstrual
irregularities in women and can lower fertility in both
men and women. How this occurs is not well-
understood, but inhibition of sex hormone production
may play a contributory role [ 62,63 ]. (See "Use of
antiinflammatory and immunosuppressive drugs in
rheumatic diseases during pregnancy and lactation",
section on 'Glucocorticoids' .)
Pregnancy — Glucocorticoid use in pregnancy may
increase the risk of cleft palate in offspring, but the
absolute risk is likely low. There is no convincing
evidence that glucocorticoids cause fetal adrenal
insufficiency. (See "Use of antiinflammatory and
immunosuppressive drugs in rheumatic diseases
during pregnancy and lactation", section on
'Glucocorticoids' .)
Musculoskeletal
Osteoporosis — One of the more serious
glucocorticoid-induced adverse effects is osteoporosis,
which is discussed in detail elsewhere.
(See"Pathogenesis, clinical features, and evaluation of
glucocorticoid-induced osteoporosis" and "Prevention
and treatment of glucocorticoid-induced
osteoporosis" .)
Vertebral fractures — The occurrence of vertebral
fractures in glucocorticoid-treated patients with bone
mineral density that is within the normal range
suggests that mechanisms in addition to
glucocorticoid-induced osteopenia and osteoporosis
contribute to increased bone fragility [ 64 ]. Increased
osteocyte and osteoblast death by apoptosis and
inhibition of osteoblast generation may allow
accumulation of microfractures and may increase the
risk of fracture [ 65,66 ]. (See "Pathogenesis, clinical
features, and evaluation of glucocorticoid-induced
osteoporosis" .)
Osteonecrosis — Osteonecrosis (avascular or
ischemic necrosis of bone) is a significant problem,
particularly with high doses of glucocorticoids.
Glucocorticoid-induced osteonecrosis is discussed
separately. (See "Osteonecrosis (avascular necrosis of
bone)", section on 'Corticosteroids' .)
Growth in children — Growth impairment is
commonly seen in children receiving glucocorticoids.
The effect is most pronounced with daily therapy, may
be less with an alternate-day regimen, and can occur
with inhaled glucocorticoids. In boys, the loss of
height (mean 4 cm in one study) may be permanent.
(See "Causes of short stature", section on
'Glucocorticoid therapy' .)
Muscle weakness — Myopathy is an infrequent
complication of glucocorticoid therapy. It typically
presents as proximal motor weakness in both the
upper and lower extremities. Glucocorticoid-induced
myopathy is discussed in detail separately.
(See "Glucocorticoid-induced myopathy" .)
More acute and severe weakness noted in critically ill
patients has been attributed at least in part to the use
of glucocorticoids. Variously referred to as critical
illness myopathy and acute quadriplegic myopathy, it
has also been suspected to be due to an interaction
between glucocorticoids and neuromuscular blocking
agents. This is discussed in more detail elsewhere.
(See "Neuromuscular weakness related to critical
illness", section on 'Critical illness myopathy' .)
Central nervous system — Glucocorticoids induce a
range of psychiatric and cognitive symptoms, which
depend upon dose and duration of therapy [ 67]. In
most patients, these symptoms are mild and
reversible, but emotional lability; hypomania; mania;
depression; psychosis; delirium, confusion, or
disorientation (which are more common in older
patients); and cognitive changes including memory
deficits may occur [ 68,69 ]. Disturbances in sleep are
reported, especially with split doses that may interfere
with the normal pattern of diurnal cortisol production.
Akathisia (motor restlessness) is a common
glucocorticoid side effect. The risk of developing a
given neuropsychiatric disorder following
glucocorticoid therapy may be increased among
patients with a past history of that condition [ 69 ].
Older patients may be at higher risk for depression;
mania; and delirium, confusion, or disorientation
[ 69 ]. The following conditions and observations
illustrate the range of reports:

 Mood disorders — Patients receiving


glucocorticoids often experience an improved
sense of well-being within several days of
starting the medications, even prior to
improvement in the status of the underlying
disease; mild euphoria or anxiety may also be
seen [ 68,70,71 ]. Hypomanic reactions and
activated states are more common early in
therapy than is depression, but the prevalence
of depression is greater in patients on more
longstanding therapy, even on low to moderate
doses [ 68,70,72 ]. Patients with a family
history of depression or alcoholism are at
increased risk for affective diseases when given
glucocorticoids [ 73 ].

More severe psychiatric symptoms can occur


quickly, within a few days, in patients receiving
high doses of glucocorticoids. As an example, in
one prospective but uncontrolled study of 50
patients receiving over 75 to 100 mg
of prednisone or equivalent for greater than a
week for various ophthalmologic indications,
hypomanic symptoms were induced in about 30
percent, and depressive symptoms in about 10
percent, of patients by the end of one week
[ 74 ]. No patient became overtly psychotic,
demented, or delirious.
 Psychosis — Psychosis can occur but does so
almost exclusively at doses of prednisone above
20 mg/day given for a prolonged period
[ 4,75,76 ]. Approximately 10 percent of
patients have persistent symptoms that may
require treatment despite reduction of
glucocorticoid dose [ 75 ]. Response to
antipsychotic drug treatment is typically
complete and occurs within two weeks of
initiation of neuroleptics. Hypoalbuminemia may
be a risk factor for glucocorticoid-induced
psychosis in patients with systemic lupus
erythematosus (SLE) [ 77 ]. Patients with SLE
who are on higher doses present a particular
problem, since it is often difficult to differentiate
psychosis due to prednisone from
neuropsychiatric lupus. (See "Overview of
psychosis", section on 'Substance induced
psychotic disorder' and "Neuropsychiatric
manifestations of systemic lupus
erythematosus" .)
 Memory impairment — Another report found that
patients treated with prednisone doses of 5 to
40 mg/day for at least one year had a partial
loss of explicit memory; older patients were
more susceptible to memory impairment with
less protracted treatment [ 67,78 ]. The effect
on memory began as early as three months
after the initiation of therapy. Approximately 1
percent of patients may be affected by more
severe and persisting cognitive disturbances
beginning during treatment with glucocorticoids
that have been termed steroid dementia; in
some patients, this condition may not remit for
between 1 and 11 months after discontinuing
the medication.
 Other symptoms — In a retrospective analysis
involving 372,696 patients in general practices
in the United Kingdom, there was a five- to
sevenfold increased risk of completed or
attempted suicide among patients receiving
glucocorticoids, compared with patients with the
same diagnoses who were not receiving such
medications; however, the absolute risk was
extremely low, approximating 0.1 cases per 100
patient-years of therapy [ 69 ]. Younger
patients were at higher risk. The observational
nature of the study and potential for unknown
confounding variables limits study
interpretation.

Rare cases of pseudotumor cerebri have been


associated with glucocorticoid use, although
higher doses are often effective in alleviating
this generally self-limiting disorder [ 79 ].
Akathisia can occur even in patients taking low
doses. An increased risk of panic disorder may
be present [ 69].

Glucose metabolism — Glucocorticoids cause a


dose dependent, usually mild increase in fasting
glucose levels and a greater increase in postprandial
values in patients without pre-existing diabetes
mellitus, but the development of de novo diabetes in a
patient with initially normal glucose tolerance is
uncommon [ 80 ]. Patients with diabetes mellitus or
glucose intolerance exhibit higher blood glucose levels
while taking glucocorticoids, leading to increased
difficulty with glycemic control. In addition, new-onset
hyperglycemia or, rarely, a nonketotic hyperosmolar
state or diabetic ketoacidosis develops without
warning in patients with early subclinical diabetes or
glucose intolerance [ 60,80,81 ].
Glucocorticoids have a variety of actions that lead to
hyperglycemia or an exacerbation of pre-existing
diabetes. The mechanism by which glucocorticoids
cause hyperglycemia is multifactorial, including
augmentation of hepatic gluconeogenesis, inhibition of
glucose uptake in adipose tissue, and alteration of
receptor and post-receptor functions [ 1,82-84 ]. It is
also possible that some underlying disorders for which
glucocorticoids are used, such as rheumatoid arthritis,
may independently predispose to a higher rate of
glucose intolerance [ 85 ].
The relative risk of new onset diabetes following the
initiation of glucocorticoid therapy was evaluated in a
study of Medicaid recipients [ 81 ]. The relative risk of
initiating glucose lowering therapy rose progressively
with the glucocorticoid dose from 1.8 in patients
treated with the equivalent of less than
10mg/day of prednisone to 10.3 in those with the
equivalent of more than 30 mg/day of prednisone.
Risk factors for new onset hyperglycemia during
glucocorticoid therapy are thought to be the same as
those for other patients, including a family history of
diabetes, increased age, obesity, and a history of
gestational diabetes [ 86 ].
Glucocorticoid-induced diabetes improves with
reduction in the dose of glucocorticoid and usually
reverses when the medication is stopped, although
some patients develop persistent diabetes [ 87,88 ].
Transient hyperglycemia can occur after intraarticular
glucocorticoid therapy.
Symptomatic diabetes mellitus, or asymptomatic but
clinically significant hyperglycemia, that is
glucocorticoid-induced is generally treated
pharmacologically in the same way as it is in patients
with diabetes mellitus or glucose intolerance in the
absence of glucocorticoid therapy. (See "Overview of
medical care in adults with diabetes mellitus", section
on 'Glycemic control' and "Management of type 2
diabetes mellitus in children and adolescents", section
on 'Pharmacologic therapy' .)
Infection and immune response — Systemic
glucocorticoids have many effects upon innate and
acquired immunity that predispose to infection,
resulting in a dose-dependent increase in the risk of
infection, especially with common bacterial, viral, and
fungal pathogens. Glucocorticoids may be associated
with a greater infection risk among patients with
rheumatoid arthritis (RA), compared with other
antirheumatic medications, such as the anti-TNF alpha
agents [ 89 ]. In one large study of RA patients,
current and recent doses were most strongly
associated with such risk, but the data also suggested
a cumulative risk effect from doses taken during the
preceding two to three years [ 90 ]. The risk of
infection with glucocorticoid therapy and the
mechanisms underlying such risk are discussed in
more detail elsewhere. (See "Glucocorticoid effects on
the immune system" .)
In addition to glucocorticoid dose, factors influencing
infection risk include the underlying disorder, the
presence of concomitant immunosuppressive
therapies, and the location of the patient (ie, whether
the patient is hospitalized). Older patients and those
with lower functional status are also at higher risk for
infection. In addition, patients taking glucocorticoids
may not manifest signs and symptoms of infection as
clearly, due to the inhibition of cytokine release and
associated reduction in inflammatory and febrile
responses. This can impair early recognition of
infection. (See "Glucocorticoid effects on the immune
system", section on 'Infection risk' and "Glucocorticoid
effects on the immune system" .)
Inhaled and topical glucocorticoids are usually not
implicated in increased risk of systemic infections, in
contrast to the effects seen with systemic agents. The
side effects of inhaled and topical glucocorticoids are
reviewed elsewhere. (See "Major side effects of
inhaled glucocorticoids" and "General principles of
dermatologic therapy and topical corticosteroid use",
section on 'Side effects' .)
Neutrophilia — Pharmacologic doses of
glucocorticoids often result in an increased white
blood cell count (leukocytosis) that is due primarily to
an increase in neutrophils (neutrophilia). This
phenomenon is due to a decreased proportion of
neutrophils that are adhering to the endothelium. This
effect of glucocorticoids is discussed in detail
elsewhere. (See "Causes of neutrophilia", section on
'Glucocorticoids and other drugs' .)
Vaccination — Glucocorticoid dose and duration, as
well the patient's underlying disease, appear to be
important determining factors in predicting response
to vaccination. These issues are discussed in detail
elsewhere. (See "Glucocorticoid effects on the
immune system", section on 'Impact on vaccination' .)
The safety of live virus vaccines in specific patient
groups is described briefly below but is reviewed in
detail separately. (See "Measles-mumps-rubella
vaccination in high risk adults" and "Prevention of
varicella-zoster virus infection:
Chickenpox" and "Prevention of varicella-zoster virus
infection: Herpes zoster" and "Immunizations after
hematopoietic cell
transplantation" and "Immunizations in solid organ
transplant candidates and
recipients" and"Immunizations in patients with
cancer" and "Medical management of immune
deficiency", section on
'Vaccination' and "Nonpharmacologic and preventive
therapies of rheumatoid arthritis", section on
'Vaccinations' .)
In general, live virus vaccines may be administered to
patients who have taken:

 Prednisone or its equivalent in doses of less than


20 mg/day for 14 days or less
 Glucocorticoids used for long-term physiologic
replacement
 Glucocorticoids administered topically, by aerosol
or by intraarticular, bursal or tendon injection,
provided that there is no clinical or laboratory
evidence of immunosuppression

If higher doses of glucocorticoids are taken, MMR,


Zoster, and other live virus vaccines should not be
administered for one month after the cessation of
glucocorticoid therapy. The immune response to other
vaccines may be compromised by glucocorticoid
administration in doses in excess of those noted
above.
MONITORING AND PREVENTION OF ADVERSE
EFFECTS — We try to limit the adverse effects of
glucocorticoids by the following steps:

 Use of the lowest dose of glucocorticoids for the


shortest period of time needed to achieve the
treatment goals
 Treatment of those pre-existing comorbid
conditions that may increase risk when
glucocorticoids are required
 Monitoring of patients under treatment for
adverse effects that may benefit from additional
intervention

Pre-existing conditions or risk factors for adverse


effects that should be assessed or treated when
glucocorticoids are to be instituted include (see
appropriate topic reviews) [ 91 ]:

 Diabetes mellitus
 Hypertension
 Dyslipidemia
 Heart failure
 Cataract or glaucoma
 Peptic ulcer disease
 Use of nonsteroidal antiinflammatory drugs
 Presence of infection
 Low bone density or osteoporosis

Much of the monitoring performed in patients on


glucocorticoids is already performed as part of the
ongoing routine preventive care appropriate for age
and the underlying medical condition. (See "Overview
of preventive medicine in adults" .)
During treatment with glucocorticoids and depending
upon individual risk factors such as dose and duration
of glucocorticoid usage, other medications being used,
and comorbidities, particular attention should be given
to (see appropriate topic reviews) [ 91 ]:

 Body weight
 Blood pressure
 Heart failure and peripheral edema
 Serum lipids
 Diabetes or glucose intolerance
 Glaucoma
 Fracture risk

HYPOTHALAMIC-PITUITARY-ADRENAL AXIS
SUPPRESSION — Administration of exogenous
glucocorticoids can suppress the hypothalamic-
pituitary-adrenal axis (HPA). Abrupt cessation, or too
rapid withdrawal, of glucocorticoids in such patients
may cause symptoms of adrenal insufficiency. The
approach to withdrawal of glucocorticoids, HPA
suppression, and the clinical manifestations of adrenal
insufficiency are presented separately.
(See"Glucocorticoid withdrawal" and "Pharmacologic
use of glucocorticoids", section on 'HPA axis
suppression' and "Clinical manifestations of adrenal
insufficiency in adults" .)
INFORMATION FOR PATIENTS — UpToDate offers
two types of patient education materials, “The Basics”
and “Beyond the Basics.” The Basics patient education
pieces are written in plain language, at the 5 th to
6 th grade reading level, and they answer the four or
five key questions a patient might have about a given
condition. These articles are best for patients who
want a general overview and who prefer short, easy-
to-read materials. Beyond the Basics patient
education pieces are longer, more sophisticated, and
more detailed. These articles are written at the
10 th to 12 th grade reading level and are best for
patients who want in-depth information and are
comfortable with some medical jargon.
Here are the patient education articles that are
relevant to this topic. We encourage you to print or e-
mail these topics to your patients. (You can also
locate patient education articles on a variety of
subjects by searching on “patient info” and the
keyword(s) of interest.)

 Basics topics (see "Patient information: Steroid


medicines (The Basics)" )

SUMMARY

 The adverse effects (AE) of glucocorticoids are


usually dose dependent, and many of the
adverse effects, even of low doses, increase
with greater duration of therapy. The effects
and AE of glucocorticoids result from both
genomic and nongenomic mechanisms that also
have a role in the therapeutic effects of these
agents. (See 'Mechanism of adverse
effects' above and 'Dose effects' above.)
 Common AEs include skin thinning and purpura;
Cushingoid appearance and weight gain; sleep
disturbance; and mood changes. Mood
disorders, cognitive changes, and, rarely,
psychosis may occur in patients on higher
doses. Hyperglycemia or new onset diabetes
mellitus is more common in patients with pre-
existing diabetes or at risk of diabetes
otherwise. Estimates of the frequency of
particular adverse effects vary between studies
and depend in part on the specific condition
being treated and the glucocorticoid treatment
regimen being used. (See 'Skin and soft
tissues' above and'Cushingoid appearance and
weight gain' above and 'Central nervous
system' above and 'Glucose
metabolism' above.)
 Cataracts are common with prolonged use (over a
year) and are dose and duration dependent AE.
Increased intraocular pressure is dose
dependent but is also influenced by underlying
risk. (See 'Eye' above.)
 There is evidence of increased risk of
cardiovascular disease, but, in some settings,
the use of antiinflammatory therapy, including
glucocorticoids, may benefit the lipid profile.
(See 'Cardiovascular disease' above
and 'Lipids' above.)
 Glucocorticoids at modest doses may cause
increased blood pressure and, especially in
patients with cardiac or renal disease, can cause
fluid retention and peripheral edema.
(See 'Kidney and systemic
hemodynamics' above.)
 Increased risk of peptic ulcer disease and gastritis
in patients receiving glucocorticoids occurs
primarily in patients concomitantly taking
nonsteroidal antiinflammatory drugs. Such
patients should receive appropriate prophylactic
therapy. (See 'Gastrointestinal tract' above.)
 Several potentially serious skeletal and muscle-
related AEs may occur and are discussed in
detail elsewhere. These include osteoporosis,
increased fracture risk, osteonecrosis,
myopathy, and, in children, effects on skeletal
development and growth.
 Immunosuppression with increased risk of
infection, neutrophilia, and the implications for
vaccination are also discussed in detail
separately. Patients receiving moderate- to
high-dose glucocorticoids should generally not
receive immunization with live virus vaccines.
(See 'Musculoskeletal' above and'Infection and
immune response' above
and 'Neutrophilia' above
and 'Vaccination' above.)
 We try to limit the adverse effects of
glucocorticoids by the following steps
(see 'Monitoring and prevention of adverse
effects' above):

 Use of the lowest dose of glucocorticoids for the


shortest period of time needed to achieve the
treatment goals
 Treatment of those pre-existing comorbid
conditions that may increase risk when
glucocorticoids are required
 Monitoring of patients under treatment for
adverse effects that may benefit from additional
intervention

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